17-63918770-T-G

Position:

• chr17-63918770-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000515.5(GH1):​c.7A>C​(p.Thr3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,613,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: GH1 NM_000515.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.06

Genes affected

GH1 (HGNC:4261): (growth hormone 1) The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. The five genes share a remarkably high degree of sequence identity. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed in the pituitary but not in placental tissue as is the case for the other four genes in the growth hormone locus. Mutations in or deletions of the gene lead to growth hormone deficiency and short stature. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024536937).
• BP6: Variant 17-63918770-T-G is Benign according to our data. Variant chr17-63918770-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 452376.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000394 (60/152284) while in subpopulation NFE AF= 0.000529 (36/68014). AF 95% confidence interval is 0.000392. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GH1	NM_000515.5	c.7A>C	p.Thr3Pro	missense_variant	1/5	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4	c.7A>C	p.Thr3Pro	missense_variant	1/5		NP_072053.1
GH1	NM_022560.4	c.7A>C	p.Thr3Pro	missense_variant	1/4		NP_072054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10	c.7A>C	p.Thr3Pro	missense_variant	1/5	1	NM_000515.5	ENSP00000312673	P1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000232 AC: 58 AN: 249884 Hom.: 1 AF XY: 0.000222 AC XY: 30 AN XY: 135138

Gnomad AFR exome AF: 0.000254

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000269 AC: 393 AN: 1460778 Hom.: 0 Cov.: 35 AF XY: 0.000263 AC XY: 191 AN XY: 726758

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000283

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74478

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000119 Hom.: 1

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000247 AC: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 23, 2018

The T3P variant in the GH1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 10/23,584 alleles (0.042%) from individuals of African background and 10/34,282 alleles (0.029%) from individuals of Latino background, with one homozygous control individual reported, in the gnomAD dataset (Lek et al., 2016). The T3P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret T3P as a variant of uncertain significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 22, 2023

Variant summary: GH1 c.7A>C (p.Thr3Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 249884 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in GH1 causing Idiopathic Growth Hormone Deficiency phenotype (6.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.7A>C in individuals affected with Idiopathic Growth Hormone Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17223997, 18950677). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	1.8
DANN	Benign	0.32
DEOGEN2	Benign	0.072	.;.;.;T;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.49	T;T;T;T;T;.
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.025	T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.81	.;N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.55	N;N;N;N;N;.
REVEL	Uncertain	0.33
Sift	Benign	0.65	T;T;T;T;T;.
Sift4G	Benign	0.26	T;T;T;T;T;D
Polyphen		0.0, 0.026, 0.044	.;.;.;B;B;B
Vest4		0.19
MVP		0.22
MPC		0.14
ClinPred		0.0013	T
GERP RS		-0.16
Varity_R		0.10
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2001345; hg19: chr17-61996130;